NZ584157A - Organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the same - Google Patents
Organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the sameInfo
- Publication number
- NZ584157A NZ584157A NZ584157A NZ58415708A NZ584157A NZ 584157 A NZ584157 A NZ 584157A NZ 584157 A NZ584157 A NZ 584157A NZ 58415708 A NZ58415708 A NZ 58415708A NZ 584157 A NZ584157 A NZ 584157A
- Authority
- NZ
- New Zealand
- Prior art keywords
- organic amine
- pyrazinecarbonitrile
- fluoro
- hydroxy
- dicyclohexylamine
- Prior art date
Links
- -1 amine salt Chemical class 0.000 title claims abstract description 25
- LJZHACRGZWYTAX-UHFFFAOYSA-N 5-fluoro-2-oxo-1h-pyrazine-3-carbonitrile Chemical compound OC1=NC=C(F)N=C1C#N LJZHACRGZWYTAX-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 150000001412 amines Chemical class 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 23
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims abstract description 18
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 claims abstract description 15
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 claims abstract description 9
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical group CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- ONECIHYIQJRNTP-UHFFFAOYSA-N 3,6-difluoropyrazine-2-carbonitrile Chemical compound FC1=CN=C(F)C(C#N)=N1 ONECIHYIQJRNTP-UHFFFAOYSA-N 0.000 claims abstract description 8
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- 150000007942 carboxylates Chemical class 0.000 description 5
- PMSVVUSIPKHUMT-UHFFFAOYSA-N cyanopyrazine Chemical compound N#CC1=CN=CC=N1 PMSVVUSIPKHUMT-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 150000003462 sulfoxides Chemical class 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 235000011056 potassium acetate Nutrition 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- UZHXXRRBFJSFCV-UHFFFAOYSA-N 3,6-dichloropyrazine-2-carbonitrile Chemical compound ClC1=CN=C(Cl)C(C#N)=N1 UZHXXRRBFJSFCV-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- AVBGNFCMKJOFIN-UHFFFAOYSA-N triethylammonium acetate Chemical compound CC(O)=O.CCN(CC)CC AVBGNFCMKJOFIN-UHFFFAOYSA-N 0.000 description 2
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- KZBREXQQUFIWKD-UHFFFAOYSA-N 5-bromo-2-oxo-1h-pyrazine-3-carboxamide Chemical compound NC(=O)C1=NC(Br)=CN=C1O KZBREXQQUFIWKD-UHFFFAOYSA-N 0.000 description 1
- OSFLEHUTGSKIPE-UHFFFAOYSA-N 5-nitro-2-oxo-1h-pyrazine-3-carboxamide Chemical compound NC(=O)C1=NC([N+]([O-])=O)=CN=C1O OSFLEHUTGSKIPE-UHFFFAOYSA-N 0.000 description 1
- ZKFNUNLVMJCMLX-UHFFFAOYSA-N 6-fluoro-3-phenylmethoxypyrazine-2-carbonitrile Chemical compound N#CC1=NC(F)=CN=C1OCC1=CC=CC=C1 ZKFNUNLVMJCMLX-UHFFFAOYSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- SVYKKECYCPFKGB-UHFFFAOYSA-N N,N-dimethylcyclohexylamine Chemical compound CN(C)C1CCCCC1 SVYKKECYCPFKGB-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical class NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- MXHTZQSKTCCMFG-UHFFFAOYSA-N n,n-dibenzyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 MXHTZQSKTCCMFG-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- UDWXLZLRRVQONG-UHFFFAOYSA-M sodium hexanoate Chemical compound [Na+].CCCCCC([O-])=O UDWXLZLRRVQONG-UHFFFAOYSA-M 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed is an organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile; wherein the organic amine is dipropylamine, dibutylamine, dicyclohexylamine, dibenzylamine or N-benzylmethylamine. Further disclosed is a process for producing an organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, which comprises reacting 3,6-difluoro-2-pyrazinecarbonitrile with water in the presence of a base, and then forming a salt with an organic amine; wherein the organic amine is dipropylamine, dibutylamine, dicyclohexylamine, dibenzylamine or N-benzylmethylamine.
Description
New Zealand Paient Spedficaiion for Paient Number 584157 W5540 18/8 1 DESCRIPTION ORGANIC AMINE SALT OF 6-FLUORO-3-HYDROXY-2-PYRAZINECARBONITRILE AND METHOD FOR PRODUCING THE SAME TECHNICAL FIELD id="p-1"
id="p-1"
[0001] The present invention relates to an organic amine salt of 6-fluoro-3-hydroxy-2-5 pyrazinecarbonitrile, which is useful as an intermediate for the preparation of pharmaceuticals, and a process for producing such an amine salt.
BACKGROUND ART id="p-2"
id="p-2"
[0002] 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (hereinafter referred to as T-705) is a compound which is useful for the prevention and treatment of viral infectious diseases, particularly influenza viral infectious diseases. It is known that T-705 can be 15 produced from, for instance, 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile (PATENT DOCUMENT 1). id="p-3"
id="p-3"
[0003] As a process for producing 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, for instance, the 20 following (1) and (2) processes are known: (1) a process in which 3,6-difluoro-2-pyrazinecarbonitrile is W5540 2 reacted with benzyl alcohol and the reaction product is debenzylated; and (2) a process in which 3,6-difluoro-2-pyrazinecarbonitrile is subjected to a reaction with water (PATENT DOCUMENT 1).
These known processes, however, have some disadvantages, for example, those as mentioned below: (A) the intermediate product 3-benzyloxy-6-fluoro-2-pyrazinecarbonitrile is a labile compound; (B) troublesome operations such as extraction, column 10 chromatography and removal of the solvent by distillation are necessary; (C) harmful hydrogen fluoride is generated when the reaction mixture is acidified; and (D) the yield is low.
Further, it is not easy to isolate 6-fluoro-15 3-hydroxy-2-pyradinecarbonitrile from a reaction mixture in a high yield by a simple operation because this compound is soluble in water and many organic solvents.
PATENT DOCUMENT 1: International Publication No. WO 20 01/60834 DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION id="p-4"
id="p-4"
[0004] A more excellent intermediate for the 25 preparation of T-705 and a process for producing such an intermediate have been strongly desired.
W5540 3 MEANS FOR SOLVING THE PROBLEMS id="p-5"
id="p-5"
[0005] Under these circumstances, the present inventors have pursued concentrated studies on the subject matter and, as a result, found that an organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile has excellent crystallinity and can serve as a useful intermediate for the preparation of T-705. They have also found that an organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile can be produced easily in a high yield by reacting 3,6-difluoro-2-pyrazinecarbonitrile with water in the presence of a base and then adding an organic amine. These findings have led them to complete the present invention.
ADVANTAGES OF THE INVENTION id="p-6"
id="p-6"
[0006] The organic amine salts of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile according to the present invention have excellent crystallinity, can be isolated 20 from a reaction mixture in a high yield by a simple operation, and are useful as an intermediate for the preparation of T-705. Also, the process of producing the organic amine salts of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile according to the present invention 25 has the advantages in that: (1) the process has no involvement of a labile intermediate; (2) no troublesome operations such as extraction, column W5540 4 chromatography and removal of the solvent by distillation are needed; (3) no harmful hydrogen fluoride is formed; (4) the yield is high; and (5) the obtained organic amine salts are high in purity. This 5 process of the present invention, therefore, is useful as a process for industrially producing the organic amine salts of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile.
BEST MODE FOR CARRYING OUT THE INVENTION 10 [0007] The present invention will be explained in detail below.
In the present description of the invention, the "organic amines" designate the following unless 15 otherwise noted: tertiary amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, tribenzylamine and N,N-dimethylcyclohexylamine; secondary amines such as dimethylamine, diethylamine, dipropylamine, dibutylamine, dibenzylamine, N-benzylmethylamine and dicyclohexylamine; primary amines such as methylamine, ethylamine, propylamine, butylamine, benzylamine and aniline; and pyridine and the like. id="p-8"
id="p-8"
[0008] In the organic amine salts of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile provided as the compounds of the present invention, the following W5540 compounds are preferred.
The compounds having as an organic amine a secondary amine, particularly dipropylamine, dibutylamine, dicyclohexylamine, dibenzylamine and N-5 benzylmethylamine are preferred, and those having dicyclohexylamine are especially preferred. id="p-9"
id="p-9"
[0009] of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile by reacting 3,6-difluoro-2-pyrazinecarbonitrile with water in the present of a base and then adding an organic 15 amine, wherein a secondary amine is used as the organic amine, is preferred. More preferred is a process using dipropylamine, dibutylamine, dicyclohexylamine, dibenzylamine or N-benzylmethylamine as a secondary amine. A process using dicyclohexylamine is even more A preferred production process according to the present invention is shown below. id="p-10"
id="p-10"
[0010] A process for producing an organic amine salt preferred. id="p-11"
id="p-11"
[0011] Next, a production process according to the present invention is explained. id="p-12"
id="p-12"
[0012] F Organic amine [1] [2] [3] W5540 6 id="p-13"
id="p-13"
[0013] An organic amine salt of the compound of the formula [3] can be produced by reacting the compound of the formula [1] with water in the presence of a base to 5 form the compound of the formula [2] , and then further reacting it with an organic amine.
This process of the present invention will be described in detail below. id="p-14"
id="p-14"
[0014] [Step 1] The compound of the formula [2] can be produced by reacting the compound of the formula [1] with water in the presence of a base.
This reaction is usually carried out in the 15 presence of a solvent. All types of solvents can be used as far as they do not exert any adverse effect to the reaction. Examples of such solvents include nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 20 dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; ketones such as acetone and 2-butanone; alcohols such as ethanol, propanol, 2-propanol and butanol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and 25 sulfoxides such as dimethyl sulfoxide. Mixtures of these solvents can be used. The preferred solvents for use in the present invention are aromatic hydrocarbons, ethers, amides and sulfoxides. Among these solvents, W5540 amides and sulfoxides are more preferred, and N,N-dimethylformamide is even more preferred. The amount of the solvent used is not definitely specified, but it is used desirably in an amount 1 to 50 times (v/w), 5 preferably 1 to 15 times (v/w) per the amount of the compound of the formula [1]. id="p-15"
id="p-15"
[0015] The bases used in the above reaction are not subject to any specific restrictions provided that they 10 are the reagents commonly used for hydroxylation in the nucleophilic displacement reactions of the aromatic halogen compounds. Examples of such bases include organic bases such as diisopropylethylamine and triethylamine; quaternary ammonium hydroxides such as 15 benzyltrimethylammonium hydroxide; carboxylates such as potassium formate, sodium formate, formic acid-triethylamine, potassium acetate, sodium acetate, acetic acid-triethylamine, sodium propionate, sodium hexanoate, sodium benzoate and benzoic acid-20 triethylamine; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, dipotassium hydrogenphosphate and tripotassium phosphate. Carboxylates are preferred for 25 use as a base. Potassium formate, formic acid-triethylamine, potassium acetate and acetic acid-triethylamine are more preferred. In the present invention, a base is used in an amount of 1 mole or W5540 8 more, desirably 1 to 10 moles to one mole of the compound of the formula [1].
Carboxylates may be prepared in the reaction system. id="p-16"
id="p-16"
[0016] The amount of water used for the above reaction is not specifically defined; it suffices to use water in an amount of one mole or more, desirably 1 to 50 moles to one mole of the compound of the formula 10 [1].
In case of using a carboxylate, it is possible to produce the compound of the formula [2] by reacting the compound of the formula [1] with the carboxylate in the absence of water and then conducting 15 reaction with water.
The reaction temperature is not specifically defined, but it is required to be not higher than 200°C, desirably between 0 and 150°C.
The reaction time is also not specified in 20 the present invention; a duration between 5 minutes and 50 hours is enough for the reaction. The preferred reaction time is 5 minutes to 24 hours.
The compound of the formula [2] can be isolated and purified, but it is desirably offered to 25 use for the next reaction without isolation. id="p-17"
id="p-17"
[0017] [Step 2] An organic amine salt of the compound of the W5540 9 formula [3] can be produced by subjecting the compound of the formula [2] to a reaction with an organic amine.
This reaction is usually carried out in the presence of a solvent. All types of solvent can be 5 used for the reaction provided that their presence is not detrimental to the reaction in any way. Examples of such solvents are nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; ketones such as acetone and 2-butanone; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides 15 such as dimethyl sulfoxide; and water. Mixtures of these solvents are also usable. A preferred solvent for use in the present invention is a mixture of at least one solvent selected from aromatic hydrocarbons, ketones, alcohols, amides and sulfoxides with water. A 20 mixture of an aromatic hydrocarbon, a ketone or an amide with water is more preferred, and a mixture of toluene, acetone or N,N-dimethylformamide with water is even more preferred. The amount of the solvent used in the present invention is not defined, but it is 25 desirably 1 to 100 times (v/w), preferably 1 to 50 times (v/w) per the amount of the compound of the formula [2]. id="p-18"
id="p-18"
[0018] W5540 The amount of an organic amine used in the above reaction is also not defined, but use of an organic amine in an amount of one mole or more to one mole of the compound of the formula [2] is enough.
Desirably an organic amine is used in an amount of one to 2 moles to one mole of the compound of the formula [2] .
The reaction temperature is not specifically defined, but it is required to be not higher than 150°C, 10 desirably between 0 and 100°C.
The reaction time is also not specified in the present invention; a duration between one minute and 50 hours is enough for the reaction. The preferred reaction time is one minute to 24 hours. id="p-19"
id="p-19"
[0019] This reaction is desirably carried out under a basic condition. For instance, desirably a base selected from ammonia water, potassium hydroxide, sodium hydroxide, potassium acetate and sodium acetate 20 is added to the reaction system. id="p-20"
id="p-20"
[0020] The organic amine salts of the compounds of the formula [3] obtained from the above-described production process can be isolated by filtering off and 25 collecting the solids. id="p-21"
id="p-21"
[0021] The compound of the formula [1] used as a starting material of the product of the present W5540 11 invention can be produced from 3,6-dichloro-2-pyrazinecarbonitrile or the like by, for instance, the process disclosed in PATENT DOCUMENT 1. 3,6-dichloro-2-pyrazinecarbonitrile can be produced by combining the 5 per se known processes (PATENT DOCUMENT 1). For instance, the above compound can be produced by reacting 3-hydroxy-6-nitro-2-pyrazinecarboxamide or 6-bromo-3-hydroxy-2-pyrazinecarboxamide with a halogenating agent such as phosphorus oxychloride. In these productions, the compound of the formula [1] and 3,6-dichloro-2-pyrazinecarbonitrile can be isolated and purified, but they may be directly used for the next reaction without isolation. id="p-22"
id="p-22"
[0022] In the process for producing the compound of the formula [3] from the compound of the formula [1], the yield of the production process described in PATENT DOCUMENT 1 was 46% (PATENT DOCUMENT 1; Example II-5(a) ) .
In contrast, in the process for producing an organic amine salt of the compound of the formula [3] from the compound of the formula [1], the yield of the production process of the present invention was as high as 83% (Example 1-1).
Thus the production process of the present invention is high in yield and useful as an industrial production process.
The compounds of the formula [2] and their W5540 12 salts and the compounds of the formula [3] include the tautomer of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile. The present invention embraces such a tautomer, and it is possible in this invention 5 to use hydrates, solvates and all the crystal forms.
EXAMPLES id="p-23"
id="p-23"
[0023] The present invention will be further explained by showing the Examples as well as the 10 Preparation Examples, but these examples are merely intended to be illustrative and not to be construed as limiting the scope of the present invention in any way. DMSO-d6: dimethyl sulfoxide-d6 id="p-24"
id="p-24"
[0024] Example 1-1 irV1 iTV°h II I II I • Dicyclohexylamine F^N^CN F N CN To a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile, a 3.8 ml water solution of 7.83 g of potassium acetate was added dropwise at 25 to 35°C, and the solution was 20 stirred at the same temperature for 2 hours. 0.38 ml of ammonia water was added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and W5540 13 the washing were joined, the pH of this solution was adjusted to 9.4 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added. Then 7.71 g of dicyclohexylamine was added dropwise and the 5 solution was stirred at 20 to 30°C for 45 minutes. Then 15 ml of water was added dropwise, the solution was cooled to 10°C, and the precipitate was filtered and collected to give 9.44 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyradinecarbonitrile as a lightly 10 yellowish white solid product.
^-NMR (DMSO-d6) 8 values: 1.00-1.36 (10H, m), 1.56-1.67 (2H, m) , 1.67-1.81 (4H, m), 1.91-2.07 (4H, m) , 3.01-3.18 (2H, m), 8.03-8.06 (1H, m), 8.18-8.89 (1H, broad) id="p-25"
id="p-25"
[0025] Example 1-2 4.11 ml of acetic acid was added at 5 to 15°C to a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then 7.27 g of triethylamine was added dropwise and the solution was 20 stirred for 2 hours. 3.8 ml of water and 0.38 ml of ammonia water were added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and 25 the washing were joined, the pH of the joined solution was adjusted to 9.2 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added to the solution, followed by dropwise addition of 7.71 g of W5540 14 dicyclohexylamine. Then 15 ml of water was added dropwise, the solution was cooled to 5°C, and the precipitate was filtered and collected to give 9.68 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-5 pyrazinecarbonitrile as a slightly yellowish white solid product. id="p-26"
id="p-26"
[0026] Examples 2 to 5 The compounds shown in Table 1 were obtained 10 in the same way as in Example 1-1. id="p-27"
id="p-27"
[0027] [Table 1] f'VOH Jj J • Organic amine FSJ CN Example No.
Organic amine Example No.
Organic amine 2 Dipropylamine 4 Dibenzylamine 3 Dibutylamine N-benzylmethylamine id="p-28"
id="p-28"
[0028] Dipropylamine salt of 6-fluoro-3-hydroxy-2-15 pyrazinecarbonitrile ■"•H-NMR (DMSO-de) 5 values: 0.39 (6H, t, J=7.5 Hz), 1.10 (4H, sex, J=7.5 Hz), 2.30-2.38 (4H, m), 7.54 (1H, d, J=8.3 Hz) id="p-29"
id="p-29"
[0029] Dibutylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile XH-NMR {DMSO-d6) 5 values: 0.36 (6H, t, J=7.3 Hz), 0.81 W5540 (4H, sex, J=7.3 Hz), 0.99-1.10 (4H, m) , 2.32-2.41 (4H, m), 7.53 (1H, d, J=8.3 Hz) id="p-30"
id="p-30"
[0030] Dibenzylamine salt of 6-fluoro-3-hydroxy-2-5 pyrazinecarbonitrile ■"■H-NMR (DMSO-de) 8 values: 4.17 (4H, s) , 7.34-7.56 (10H, m), 8.07 (1H, d, J=8.3 Hz) id="p-31"
id="p-31"
[0031] N-benzylmethylamine salt of 6-fluoro-3-hydroxy-2-10 pyrazinecarbonitrile 1H-NMR (DMSO-de) 8 values: 2.57 (3H, s) , 4.14 (2H, s) , 7.37-7.53 (5H, m) , 8.02-8.08 (1H, m) id="p-32"
id="p-32"
[0032] Preparation Example 1 F^Sl CN N^OH Dicyclohexylamine ~ ' CONKj jftc 300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25°C and the solution was stirred at the same temperature for 30 20 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30°C and one-hour stirring at 20 to 30°C. Then 39 ml of hydrochloric acid was added, 25 the seed crystals were added at 40 to 50°C, and 39 ml of
Claims (6)
1. An organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile; wherein the organic amine is dipropylamine, dibutylamine, dicyclohexylamine, dibenzylamine or N-benzylmethylamine.
2. The organic amine salt according to claim 1, wherein the organic amine is dicyclohexylamine.
3. A process for producing an organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, which comprises reacting 3,6-difluoro-2-pyrazinecarbonitrile with water in the presence of a base, and then forming a salt with an organic amine; wherein the organic amine is dipropylamine, dibutylamine, dicyclohexylamine, dibenzylamine or N-benzylmethylamine.
4. The process according to claim 3, wherein the organic amine is dicyclohexylamine.
5. An organic amine salt according to claim 1, substantially as herein described with reference to any one of the accompanying Examples thereof.
6. A process according to claim 3, substantially as herein described with reference to any one of the accompanying Examples thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007251191 | 2007-09-27 | ||
| PCT/JP2008/067251 WO2009041473A1 (en) | 2007-09-27 | 2008-09-25 | Organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ584157A true NZ584157A (en) | 2012-04-27 |
Family
ID=40511356
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ584157A NZ584157A (en) | 2007-09-27 | 2008-09-25 | Organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the same |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US8168789B2 (en) |
| EP (1) | EP2192117B1 (en) |
| JP (1) | JP5550347B2 (en) |
| KR (2) | KR101574567B1 (en) |
| CN (2) | CN104672153B (en) |
| AU (1) | AU2008304956B2 (en) |
| BR (1) | BRPI0817305B1 (en) |
| CA (1) | CA2700490C (en) |
| CY (1) | CY1115218T1 (en) |
| DK (1) | DK2192117T3 (en) |
| ES (1) | ES2470740T3 (en) |
| HR (1) | HRP20140837T1 (en) |
| IL (1) | IL204516A (en) |
| MX (1) | MX2010003333A (en) |
| NZ (1) | NZ584157A (en) |
| PL (1) | PL2192117T3 (en) |
| PT (1) | PT2192117E (en) |
| RU (1) | RU2470924C2 (en) |
| SI (1) | SI2192117T1 (en) |
| WO (1) | WO2009041473A1 (en) |
| ZA (1) | ZA201002001B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY161757A (en) * | 2010-09-30 | 2017-05-15 | Toyama Chemical Co Ltd | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
| JPWO2012043700A1 (en) * | 2010-09-30 | 2014-02-24 | 富山化学工業株式会社 | Sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide |
| CN103347884B (en) | 2010-11-12 | 2015-12-02 | 富士胶片株式会社 | Pyrazine is [2,3-d] different * oxazole derivatives also |
| CN104496917B (en) * | 2014-12-15 | 2017-06-20 | 南京华威医药科技开发有限公司 | A kind of synthetic method of Favipiravir |
| EP3309149B1 (en) | 2015-06-09 | 2021-04-07 | FUJIFILM Toyama Chemical Co., Ltd. | 6-bromo-3-hydroxy-2-pyrazinecarboxamide crystal and method for producing same |
| CN107641106A (en) * | 2016-07-22 | 2018-01-30 | 大连鸿凯化工科技发展有限公司 | The synthetic method of Favipiravir intermediate and Favipiravir |
| CN113248450B (en) * | 2020-02-07 | 2024-04-12 | 北京四环制药有限公司 | Fapila preparation method of pyrrosia lingua |
| WO2021260516A1 (en) * | 2020-06-22 | 2021-12-30 | Pi Industries Ltd. | An organic amine salt of favipiravir and a process for the purification of favipiravir |
| WO2022009036A1 (en) * | 2020-07-06 | 2022-01-13 | Optimus Drugs (P) Ltd | Synthesis of favipiravir |
| CN112645889A (en) * | 2020-12-24 | 2021-04-13 | 杭州煌森生物科技有限公司 | Refining method of Favipiravir |
| CN114478404A (en) * | 2022-03-17 | 2022-05-13 | 浙江海正药业股份有限公司 | Purification method of faviravir intermediate hydroxyl |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB879259A (en) | 1956-11-20 | 1961-10-11 | Riker Laboratories Inc | Acid addition salts of 2-dimethylaminoethanol and central nervous system stimulant compositions containing them |
| CZ282939B6 (en) * | 1992-03-04 | 1997-11-12 | Lonza A.G. | NITROGENOUS HYDROXY HETEROCYCLIC CARBOXYLIC ACIDS, PROCESS OF THEIR PREPARATION AND MICRO-ORGANISMS Ki101DSN6920 |
| BRPI0116967B8 (en) * | 2000-02-16 | 2021-05-25 | Fujifilm Toyama Chemical Co Ltd | pyrazine derivative or a salt thereof, pharmaceutical composition, and, fluoropyrazine derivative or a salt thereof |
| RU2297414C2 (en) * | 2001-02-14 | 2007-04-20 | Тояма Кемикал Ко., Лтд. | Derivatives of pyrazine or their salts, pharmaceutical composition containing these compounds and intermediate compounds for their preparing |
| JP4398631B2 (en) * | 2002-07-12 | 2010-01-13 | 富山化学工業株式会社 | Novel pyrazine derivatives or salts thereof and antiviral agents containing them |
| GB0407908D0 (en) | 2004-04-07 | 2004-05-12 | Univ York | Ionic liquids |
-
2008
- 2008-09-25 NZ NZ584157A patent/NZ584157A/en unknown
- 2008-09-25 WO PCT/JP2008/067251 patent/WO2009041473A1/en active Application Filing
- 2008-09-25 PT PT88328166T patent/PT2192117E/en unknown
- 2008-09-25 KR KR1020107006533A patent/KR101574567B1/en active IP Right Grant
- 2008-09-25 EP EP08832816.6A patent/EP2192117B1/en active Active
- 2008-09-25 MX MX2010003333A patent/MX2010003333A/en active IP Right Grant
- 2008-09-25 KR KR1020157022432A patent/KR101686813B1/en active IP Right Grant
- 2008-09-25 DK DK08832816.6T patent/DK2192117T3/en active
- 2008-09-25 CN CN201510024656.1A patent/CN104672153B/en active Active
- 2008-09-25 CN CN200880109041A patent/CN101809003A/en active Pending
- 2008-09-25 ES ES08832816.6T patent/ES2470740T3/en active Active
- 2008-09-25 JP JP2009534345A patent/JP5550347B2/en active Active
- 2008-09-25 PL PL08832816T patent/PL2192117T3/en unknown
- 2008-09-25 US US12/679,496 patent/US8168789B2/en active Active
- 2008-09-25 AU AU2008304956A patent/AU2008304956B2/en active Active
- 2008-09-25 RU RU2010116390/04A patent/RU2470924C2/en active
- 2008-09-25 CA CA2700490A patent/CA2700490C/en active Active
- 2008-09-25 BR BRPI0817305-2A patent/BRPI0817305B1/en active IP Right Grant
- 2008-09-25 SI SI200831283T patent/SI2192117T1/en unknown
-
2010
- 2010-03-16 IL IL204516A patent/IL204516A/en active IP Right Grant
- 2010-03-19 ZA ZA2010/02001A patent/ZA201002001B/en unknown
-
2014
- 2014-07-01 CY CY20141100481T patent/CY1115218T1/en unknown
- 2014-09-04 HR HRP20140837AT patent/HRP20140837T1/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NZ584157A (en) | Organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the same | |
| EP1392703A1 (en) | Crystalline acid salts of cefdinir and process for preparing cefdinir using same | |
| GB2063870A (en) | 1-aryl-4-arylsulphonyl-1h-pyrazolol-3 compounds and processes for their preparation | |
| EP3422855B1 (en) | Process for the preparation of 4-alkoxy-3-hydroxypicolinic acids | |
| KR100522846B1 (en) | Processes for preparing quaternary ammonium salts of triazine compounds | |
| SU1556538A3 (en) | Method of producing pyrimidine derivatives | |
| US20130060031A1 (en) | Process for the preparation of highly pure ambrisentan | |
| US6150528A (en) | Method for producing 5-aminomethyl-2-chloropyridines | |
| DK160503B (en) | Anhydrides of 6-fluoro-7-chloro-1-methylamino-4-oxo-1,4- dihydroquinoline-3-carboxylic acid and boric acids | |
| JP2020523353A (en) | Process for producing 3,4-dichloro-N-(2-cyanophenyl)-5-isothiazolecarboxamide | |
| WO2009027990A1 (en) | Salts of montelukast and process therefor | |
| JP3545466B2 (en) | Dihydrochromancarboxylic acids and method for producing the same | |
| EP0071741A1 (en) | Process for producing 2,4-diamino-(3,5-dimethoxy-4-methoxy-ethoxy-benzyl)-pyrimidine | |
| RU2127270C1 (en) | Method of synthesis of 1-substituted-6-fluoro-4-oxo-7-(1- -piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid, 1-substituted-6-fluoro-4-oxo-7-(4-substituted-1-piperazinyl)- -1,4-dihydroquinoline-3-carboxylate-boron-diacetate and a method of its synthesis | |
| JP2630379B2 (en) | Method for producing 3-carbamoylpyrazine-2-carboxylic acid compound | |
| JP2023152806A (en) | Method for producing 4,4'-dihydroxybiphenyl-3,3'-dicarboxylic acid | |
| JP5114902B2 (en) | Method for producing bipyridinediol derivative | |
| KR20090103679A (en) | AN IMPROVED PROCESS FOR THE PRODUCTION OF 10-HALO-BENZO[b][1,5]NAPHTHYRIDINE | |
| JP2005002074A (en) | New alkyl vinyl ether-substituted trinuclear polyphenol | |
| JP2011098895A (en) | Industrially useful method of producing 2-hydroxyethyloxyamine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| RENW | Renewal (renewal fees accepted) | ||
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 25 SEP 2016 BY CPA GLOBAL Effective date: 20150815 |
|
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 25 SEP 2017 BY CPA GLOBAL Effective date: 20160812 |
|
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 25 SEP 2018 BY CPA GLOBAL Effective date: 20170810 |
|
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 25 SEP 2019 BY CPA GLOBAL Effective date: 20180809 |
|
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 25 SEP 2020 BY CPA GLOBAL Effective date: 20190808 |
|
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 25 SEP 2021 BY CPA GLOBAL Effective date: 20200813 |
|
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 25 SEP 2022 BY CPA GLOBAL Effective date: 20210812 |
|
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 25 SEP 2023 BY CPA GLOBAL Effective date: 20220811 |
|
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 25 SEP 2024 BY CPA GLOBAL Effective date: 20230811 |